Variants in the SIRT1 Gene May Affect Diabetes Risk in Interaction With Prenatal Exposure to Famine.

0.61 MB·English

by  Botden, Ilse P.G.

Cardiovascular and Metabolic Risk
B R I E F R E P O R T
Variants in the SIRT1 Gene May Affect
Diabetes Risk in Interaction With
Prenatal Exposure to Famine
ILSE P.G. BOTDEN, MD1 A.H. JAN DANSER, PHD1 an oral glucose tolerance test (OGTT).
M. CAROLA ZILLIKENS, MD, PHD1 ERIC J.G. SIJBRANDS, MD, PHD1 Secondary outcome measures were glu-
SUSANNE R. DE ROOIJ, PHD2 TESSA J. ROSEBOOM, PHD2,3 cose metabolism parameters (120-min
JANNEKE G. LANGENDONK, MD, PHD1 glucoseandinsulinlevels,areaunderthe
curve[AUC]forglucoseandinsulin)and
BMI.
OBJECTIVEdTo investigate whether SIRT1, a nutrient-sensing histone deacetylase, influ-
encesfetalprogrammingduringmalnutrition.
Genotyping
RESEARCHDESIGNANDMETHODSdIn793individualsoftheDutchFamineBirth DNAwasavailablefrom793subjectsfor
Cohort, we analyzed the interaction between three SIRT1 single nucleotide polymorphisms Taqman allelic discrimination assays.
(SNPs)andprenatalexposuretofamineontype2diabetesrisk. Threetaggingsinglenucleotidepolymor-
phisms(SNPs)wereselected,coveringmost
RESULTSdInthetotalpopulation(exposedandunexposed),SIRT1variantswerenotasso- ofthecommonvariantsoftheSIRT1gene
ciatedwithtype2diabetes.AsignificantinteractionwasfoundbetweentwoSIRT1SNPsand
in whites (rs7895833, rs1467568, and
exposure to famine in utero on type 2 diabetes risk (P = 0.03 for rs7895833; P = 0.01 for
rs497849,asdescribedearlier)(6).Minor
rs1467568). Minor alleles of these SNPs were associated with a lower prevalence of type 2
allelefrequenciesoftheSNPswere19,36,
diabetes only in individuals who had been exposed to famine prenatally (odds ratio for
rs78958330.50[95%CI0.24–1.03],P=0.06;forrs14675680.48[0.25–0.91],P=0.02). and22%,respectively.TheSNPswerein
Hardy-Weinberg equilibrium (x2 ,3.1;
CONCLUSIONSdSIRT1maybeanimportantgeneticfactorinvolvedinfetalprogramming 1df;P.0.07).
duringmalnutrition,influencingtype2diabetesrisklaterinlife.
Statistical methods
DiabetesCare35:424–426,2012
Associationsofgeneticvariantsanddiabe-
F tes were investigated with binary logistic
etal malnutrition may predispose to the famine in the Netherlands during regression and associations with BMI,
type2diabetesbyalteringgeneexpres- WorldWarII,asdescribedindetailearlier AUC, and 120-min levels of glucose and
sionprofilesthroughepigeneticmech- (5).Atotalof2,414 singletonswereborn insulinwithlinearregression.Interactions
anisms (1–3). SIRT1, a nutrient-sensing between1November1943and28Febru- were tested by creating interaction terms
histonedeacetylase,is,inadditiontodeace- ary 1947. A total of 810 of 1,423 invited foreachgeneticvariantwiththeexposure
tylation of histones, involved in glucose subjectsagreedtoparticipateinthecohort group. The minor allele was coded 1 and
and insulin metabolism by regulating the studyin2002.Thestudywasapprovedby 0fornoncarriers.Unexposedsubjectsborn
expressionofvarioustranscriptionfactors. the local medical ethics committee. All beforeorconceivedaftertheDutchfamine
Dietary factors influence the NAD+-to- participants gave written informed con- werecoded 0and1 forexposed subjects.
NADHratioregulatingSIRT1activity (4). sent.Prenatalexposuretofaminewasde- P,0.05wasconsideredsignificant.
We hypothesized that genetic variants in finedasadailyfoodrationforthepregnant
SIRT1mayinteractwithfetalmalnutrition, motherof,1,000caloriesduringany13-
influencingtype2diabetesrisklaterinlife. weekperiodofgestation. RESULTSdAtotalof337subjectswere
This was addressed in the Dutch Famine exposedtofamineinutero,and456sub-
BirthCohort. Study parameters jectswerebornbeforeorafterthefamine.
Theprimaryoutcomemeasureofthecur- In adulthood, BMI and type 2 diabetes
RESEARCH DESIGN AND rentstudywastype2diabetes,whichwas prevalence were not different between
METHODSdThe Dutch Famine Birth defined as using antidiabetes medications subjectsexposedandnonexposedtofam-
Cohort is composed of individuals born or fasting glucose levels .7.0 mmol/L or ine. A total of 117 of 791 individuals de-
astermsingletonsinAmsterdamaround 120-min glucose levels .11.0 mmol/L in veloped diabetes in adulthood (15.8% in
theexposedand14.1%intheunexposed
group). Plasma glucoselevelsat120 min
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
oftheOGTTwere0.37mmol/L(P=0.03)
Fromthe1DepartmentofInternalMedicine,ErasmusUniversityMedicalCenter,Rotterdam,theNetherlands; higher for those exposed to famine in
the 2Department ofClinicalEpidemiology, Biostatisticsand Bioinformatics, AcademicMedicalCenter,
Amsterdam, the Netherlands; and the 3Department of Obstetrics and Gynecology, Academic Medical utero.
Center,Amsterdam,theNetherlands. Inthetotalpopulation(exposedand
Correspondingauthor:EricJ.G.Sijbrands,[email protected]. unexposed),carriersoftheminoralleleof
Received24June2011andaccepted31October2011. rs7895833(GGandAG)andrs1467568
DOI:10.2337/dc11-1203
(AAandGA)hadahigherBMIthannon-
©2012bytheAmericanDiabetesAssociation.Readersmayusethisarticleaslongastheworkisproperly
cited,theuseiseducationalandnotforprofit,andtheworkisnotaltered.Seehttp://creativecommons.org/ carriers (b for rs7895833: 0.82 kg/m2
licenses/by-nc-nd/3.0/fordetails. [95% CI 0.09–1.56], P = 0.028; b for
424 DIABETESCARE,VOLUME35,FEBRUARY2012 care.diabetesjournals.org
BotdenandAssociates
rs1467568: 0.96 kg/m2 [0.25–1.67], P = group,whereassuchatrendwasnotevi- (9) showed that suboptimal nutrition in
0.008).Therewasnoassociationbetween dent in the unexposed subjects (data not ratsduringearlydevelopmentledtoepi-
theSIRT1variantsanddiabetesandAUCs shown). geneticsilencingandreducedtheexpres-
of glucose and insulin levels during In those prenatally exposed to fam- sion of the transcription factor Hnf4a,
OGTT. ine, BMI was significantly higher in car- whichisrequiredforpancreaticb-celldif-
Next,weinvestigatedtheinteractions riers of minor alleles of rs7895833 and ferentiation and glucose homeostasis.
oftheSIRT1SNPswithprenatalexposure rs1467568(Fig.1B).Insubjects,whohad Valtat et al. (10) also showed that food
tofamineontype2diabetesriskandBMI notbeenexposedtofamineprenatally,no restrictionduringgestationimpairedglu-
atage58years.Aninteractionwasfound significant association was found, al- cosetoleranceanddecreasedb-cellmass
betweenprenatalexposuretofamineand though the direction of the effect was laterinlife.Inline,wealsofoundthatex-
rs7895833(P=0.03)andrs1467568(P= thesame(Fig.1B). posuretofamineinuteroreducedglucose
0.01)butnotwithrs497849ondiabetes tolerance(5).
risk.Instratifiedanalysesinsubjectsnot CONCLUSIONSdOur results show We previously reported an interac-
prenatally exposed to famine, the SNPs that an interaction between two SNPs in tion between variants of the PPAR-g2
and type 2 diabetes were not associated SIRT1(rs7895833andrs1467568)andin geneandtheIGF2BP2geneandexposure
(Fig. 1A). In the exposed subjects, there utero exposure to malnutrition signifi- tofamineinuteroontheprevalenceofim-
was a borderline significant association cantly influenced type 2 diabetes risk in pairedglucosetoleranceandtype2diabe-
between rs7895833 and diabetes and a adulthood. Minor allele carriers of these tes(11,12).WhetherSIRT1interactswith
significant association for rs1467568, twogeneticSIRT1variantswhohadbeen thesegenesonpathwaysinfluencingdiabe-
with diabetes risk decreasing for minor exposed to famine in utero had a 50% tesriskshouldbeelucidatedbyadditional
allele carriers (Fig. 1A). We did not ob- lower risk of developing diabetes than studies.
serve an interaction between any of the noncarriersbut,surprisingly,hadahigher Unexpectedly, associations between
SIRT1 variants and exposure to famine BMI. twoSIRT1SNPsandBMIinsubjectswho
onBMI,glucose,andinsulinvalues.How- SIRT1 is susceptible to intracellular had been exposed to famine were in the
ever, minor allele carriers of rs7895833 fluctuationsintheNAD+-to-NADHratio opposite direction as expected (13–15).
tended to have lower 120-min glucose andmayinfluencetype2diabetesriskby Nevertheless, the SIRT1 variants inter-
and insulin levels as well as lower AUC itsknownepigeneticeffectsandb-cellap- actedwithexposuretofamineondiabetes
glucose/insulin values in the exposed optosis(4,7,8).Recently,Sandovicietal. riskindependentofBMI.
Interactions have been reported be-
tween SIRT1 variants and niacin (6) and
vitamin E (16) intake. It is possible that
associations between SIRT1 variants and
diabetesriskcanonlybefoundwhenin-
teractionswithenvironmentalfactorsare
takenintoaccount,suchasfetalnutrition
inourstudy.
Although our resultsare basedonre-
lativelysmallnumbersandthereforehave
to be interpreted with caution, they sup-
port that SIRT1 plays a role in the fetal
programming of type 2 diabetes through
fetalmalnutrition.
AcknowledgmentsdTheDutchFamineBirth
Cohort study was funded by grants from
the Dutch Heart Foundation (NHS2007B087
and NHS2003B165), the European Science
Foundation(EUROCORES/STRESS),andThe
Netherlands Organization forScientificRe-
search(NWO).
Nopotentialconflictsofinterestrelevantto
thisarticlewerereported.
I.P.G.B. and M.C.Z. researched data, con-
tributed to the discussion, and wrote the
manuscript.S.R.R.andT.J.R.researcheddata,
contributed to the discussion, and reviewed
andeditedthemanuscript.J.G.L.andA.H.J.D.
contributed to the discussion and reviewed
Figure1dTherelationshipofthers7895833andrs1467568SIRT1SNPswiththeprevalence and edited the manuscript. E.J.G.S. is the
ofdiabetes(A)andBMI(B)accordingtoprenatalexposuretofamine.Oddsratios(ORs;A)and guarantor of the article, contributed to
b-coefficients(b;B)areshownforcarriersoftheminoralleles.Thenumberofsubjectspergroup the discussion, and reviewed and edited the
(i.e.,diabeticpatientsforA)areshowninsideeachbar.*P,0.05vs.noncarriers. manuscript.
care.diabetesjournals.org DIABETESCARE,VOLUME35,FEBRUARY2012 425
SIRT1variation,prenatalfamine,anddiabetes
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